The heart has a pumping function comprising periodic contraction and relaxation functions in the myocardium, which provides blood to the internal tissues and organs of the whole body and returns blood to the heart therefrom.
The heart contracts and relaxes regularly and periodically. This cardiac cycle is roughly divided into two phases; the systole and the diastole. The systole is from mitral valve closure to aortic valve closure and the diastole is from aortic valve closure to mitral valve closure. Further, the diastole consists of 4 phases; the isovolumetric relaxation phase, the rapid ventricular filling phase, the slow ventricular filling phase and the atrial contraction phase.
Among the four phases in the diastole, the initial first phase, which is the isovolumetric relaxation phase, is the beginning period of myocardial relaxation, and in the second to fourth phases of the diastole, blood flows from atrium to ventricle.
The cardiac function is separated into contractile (systolic) function and relaxing (diastolic) function. As a method for evaluating contractile and relaxing function, for the contractile function, the maximum +dP/dt, which is the first differential of left ventricular pressure in the left ventricular isovolumetric contraction phase, is used as an index. For the relaxing function, the maximum −dP/dt, which is the first differential of left ventricular pressure in the first phase of the four phases in the diastole, which is the isovolumetric relaxation phase, is used as an index of relaxing function. In addition, the left ventricular end-diastolic pressure is also used as an index of relaxing function, but is raised in both systolic heart failure and diastolic heart failure.
When the heart does not normally contract and relax, the pumping function is impaired and heart failure and shock occur.
The heart failure is developed when the contractile or relaxing/diastolic function is impaired. The symptoms are dyspnea, edema, tachycardia and the like. In addition, the heart failure is separated into systolic heart failure and diastolic heart failure depending on differences in developmental mechanisms, and cases in which cardiac contractile function is mainly impaired are called systolic heart failure, and cases in which relaxing/diastolic function is impaired are called diastolic heart failure.
Shock is a morbid state in which acute systemic circulatory failure is caused due to an acute decrease in blood pressure, and diagnosed using a systolic pressure of 90 mm Hg or less, oliguria, disturbance of consciousness, peripheral vasoconstriction and the like as criteria for diagnosis. The causes of shock include cardiogenic shock due to an acute impairment in cardiac function, and further hemorrhagic shock, septic shock, anaphylactic shock and the like.
The myocardial contractile and/or relaxing/diastolic function are impaired in heart failure and cardiogenic shock. When the myocardial contractile function is impaired, the +dP/dt decreases. On the other hand, when relaxing function is impaired, the maximum −dP/dt deteriorates (its absolute value decreases). When the left ventricular relaxing function is impaired, left ventricular end-diastolic pressure is raised.
The myocardial contractile and relaxing/diastolic function can be detected in the left ventricular myocardial wall motion by using Doppler echocardiography, and can be diagnosed by determining left ventricular pressure by using a pressure transducer-tipped catheter.
For treating heart failure and cardiogenic shock, cardiotonics are used in addition to treatment corresponding to causes thereof. Now, cardiotonic drugs include catecholamine formulations, phosphodiesterase inhibitors, calcium sensitizers, digitalis formulations, and the like. In heart failure and shock, cardiac rate increases. Catecholamine has the effect of raising cardiac rate, and cardiotonic drugs generally have a lethal arrhythmogenic effect to cause sudden death. These effects limit largely in treating heart failure and cargiogenic shock.
An agent having the effect of raising blood pressure and enhancing myocardial contraction and relaxation without increasing cardiac rate can make a desired medicine as a therapeutic agent for heart failure and shock. In addition, an agent having the effect of myocardial relaxation without increasing heart rate can make a medicine to improve relaxation impairment associated with ischemic heart disease, hypertensive heart disease or tachyarrhythmia.
It has been reported that certain types of diphenylmethyl piperazine derivatives prevent the development of myocardial necrosis and have an antitumor effect (see Patent Documents 1 and 2). There is, however, no description that these compounds have a vasopressor effect and the effect of enhancing myocardial contraction and relaxation herein.